The protein kinases represent a large family of proteins that play a central role in the regulation of a wide variety of cellular processes and maintenance of cellular function. A partial, non-limiting, list of these kinases include: non-receptor tyrosine kinases such as the Janus kinase family (Jak1, Jak2, Jak3 and Tyk2); receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGFR); and serine/threonine kinases such as b-RAF. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems. The compounds of this invention selectively inhibit the activity of one or more protein kinases over other related kinases, and are thus expected to be useful in the treatment of diseases mediated by the selectively inhibited kinase(s) while avoiding the undesirable side effects associated with the inhibition of the related kinase(s).
In particular, the Janus kinase family comprises 4 known family members: Jak 1, 2, 3, and tyrosine kinase 2 (Tyk2). These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors such as common gamma-chain receptors and the glycoprotein 130 (gp 130) trans-membrane proteins (Murray, J. Immunol. 178(5):2623-2629, 2007). Almost 40 cytokine receptors signal through combinations of these 4 Jak family members and their 7 downstream substrates: the signal transduction activators of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228(1):273-287, 2009). Cytokine binding to its receptor initiates Jak activation via trans- and auto-phosphorylation. The Jak family kinases in turn phosphorylate cytokine receptor residues, creating binding sites for sarcoma homology 2 (SH2) containing proteins, such as the STAT factors and other regulators, which are subsequently activated by Jak phosphorylation. Activated STATs enter the nucleus initiating expression of survival factors, cytokines, chemokines, and molecules that facilitate leukocyte cellular trafficking (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). Jak activation also results in cell proliferation via phosphoinositide 3-kinase (PI3K) and protein kinase B-mediated pathways.
Jak3 and Jak1 are components of the common gamma-chain cytokine receptor complexes, and blockade of either inhibits signaling by inflammatory cytokines: interleukin (IL)-2, 4, 7, 9, 15, and 21 (Ghoreschi et al., Immunol. Rev. 228(1):273-287, 2009). By contrast, other pathologically relevant cytokines, such as IL-6, depend uniquely on Jak1. Hence, Jak1 blockade inhibits signaling of many pro-inflammatory cytokines (Guschin et al., EMBO J. 14(7):1421-1429, 1995). Clinical efficacy in rheumatoid arthritis (RA) has been observed with the IL-6 receptor neutralizing antibody, tocilizumab (Maini et al., Arthritis Rheum. 54(9):2817-2829, 2006).
Humans deficient in Jak1 and Jak2 have not been described. Mice lacking Jak1 die perinatally (Schindler et al., J. Biol Chem. 282(28):20059-20063, 2007). Jak2 deficiency in mice is also lethal, with Jak2−/− embryos dying between Day 12 and Day 13 after conception because of deficits in erythropoiesis (Neubauer et al., Cell 93(3):397-409, 1998). Jak3 deficiency has been described in humans and presents as severe combined immunodeficiency in the first few months of life, with symptoms such as failure to thrive, severe and recurrent infections, thrush, and diarrhea. Infants with Jak3 deficiency have an absence of circulating T cells and NK cells and abnormal B cell function. Tyk2-deficiency additionally has been described in humans, manifesting with impaired antimicrobial responses, elevated serum IgE, and atopic dermatitis (Minegishi et al., Immunity 25(5):745-755, 2006).
Given the high degree of structural similarity between Jak1 and Jak2 (Williams et al., J. Mal. Biol. 387(1):219-232, 2009), the literature suggests that the majority of Jak1 inhibitors also inhibit Jak2 (lncyte Corp. press release, 10 Nov. 2010; Changelian et al., Science 302(5646):875-878, 2003).
Anti-cytokine therapies have become standard in the treatment of RA. In humans, a growing body of evidence suggests that Jak1 inhibition is an effective therapy for the treatment of signs and symptoms of RA. Multiple clinical trials administering Pfizer's Jak 1/3 inhibitor tofacitinib (Kremer et al., Arthritis Rheum. 60(7):1895-1905, 2009; Riese et al. Best Pract. Res. Clin. Rheumatol. 24(4):513-526, 2010), Incyte/Lilly's Jak1/2 inhibitor INCB-28050/LY3009104 (lncyte Corp. press release, 10 Nov. 2010), or Galapagos' Jak1 inhibitor GLP0634 (Galapagos Nev. press release, 22 Nov. 2011) have demonstrated statistically significant efficacy in this disease.
Tofacitinib, an inhibitor of Jak1, and Jak3, has been approved in the United States and additional countries around the world for the indication of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to methotrexate (MTX), used as monotherapy or in combination with MTX or other non-biologic DMARDs. Safety data from Phase 2 and Phase 3 studies in patients (Fleischmann, Curr. Opin. Rheumatol. 24(3):335-341, 2012; Kremer et al., Arthritis Rheum. 64(4):970-981, 2012; Fleischmann et al., Arthritis Rheum. 64(3):617-629, 2012) with RA for tofacitinib compared with placebo have indicated that the most common serious adverse reactions are infections, including pneumonia, cellulitis, herpes zoster, and urinary tract infection. In addition, tuberculosis (including cases of disseminated tuberculosis) and opportunistic infections such as other mycobacterial infections, cryptococcus, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus were reported. Lymphoma and other malignancies have been observed in patients treated with tofacitinib. Epstein-Barr virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications. Gastrointestinal perforations in patients receiving tofacitinib also were reported. In addition, laboratory abnormalities have been described, including dose-related decreases in absolute neutrophil counts as well as hemoglobin. Furthermore, small increases in liver transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) and serum creatinine, and elevated LDL, HDL, and total cholesterol levels have been reported.
A Phase 2 study of VX-509 (inhibitor of Jak3) in patients with RA also has shown an increased risk of infections and increases in lipid levels (Fleischmann et al., Arthritis Rheum. 63:LB3, 2011).
A 52-week, open-label, long-term extension Phase 2b study of baricitinib—an orally administered selective Jak1 and Jak2 inhibitor—in 201 patients with active RA found no opportunistic infections, cases of tuberculosis, or lymphomas. Clinically significant laboratory abnormalities were infrequently observed (increased ALT, anemia, increased creatine kinase [CK], pancytopenia, reported in one subject each); one subject discontinued due to a laboratory abnormality (increased ALT). One death occurred and was attributed to presumed myocardial infarction (Keystone et al., Ann. Rheum. Dis. 71(Suppl 3):152, 2012; Genovese et al., Arthritis Rheum. 64 (Suppl 10):2487, 2012; Taylor et al., abstract OP0047, EULAR 2013, the Annual Congress of the European League Against Rheumatism. 2013 Jun. 12-15; Madrid, Spain).
Despite the seemingly numerous treatment options, however, many RA patients fail to experience substantial decreases in disease activity. Although earlier studies have shown that Jak blockade may be effective in managing disease and achieving remission, the first generation Jak inhibitors (such as tofacitinib and baricitinib) have failed to reach their full potential, at least partly due to their tolerability and safety issues that limit dose.
Specifically, the first generation Jak inhibitors tofacitinib and baricitinib have been characterized as Jak1/Jak3 and Jak1/Jak2 inhibitors, respectively (Fridman et al., J. Immunol., 184:5298-5307, 2010; Meyer et al., J. lnflamm. (Lond.) 7:41, 2010; and Taylor et al., Rheumatology 52:i44-i55, 2013). Despite the initial encouraging results, these first generation Jak inhibitors have failed to reach their full potential due to tolerability issues that limited dose (Fleischmann et al., Curr. Opin. Rheumatol. 24:335-341, 2012; Riese et al., Best Pract. Res. Clin. Rheumatol. 24:513-526, 2010). JAKs are known to play roles in the regulation of over forty pathways (Murray, J. Immunol. 178:2623-2629, 2007). However, despite the high selectivity of these two compounds for JAKs over other kinase families, these inhibitors may not be optimally selective for kinases within the JAK family. For instance, incidence of severe anemia was reported to be a dose limiting factor during Tofacitinib Phase II development in RA (Pfizer, Investigators Brochure. In FDA Advisory Board (Bethesda Md.), 2012; Riese et al., Best Pract. Res. Clin. Rheumatol. 24:513-526, 2010). Moreover, increases in herpes virus infections, potentially secondary to decreases in NK cell counts, were reported in Phase III tofacitinib trials (O'Shea et al., Ann. Rheum. Dis. 72(Suppl 2):ii 111-115, 2013; Pfizer, Investigators Brochure. In FDA Advisory Board (Bethesda Md.), 2012). It is reasonable that these effects could arise due to inhibition of EPO and IL-15 signaling via Jak2 and Jak3 respectively (Jost and Altfeld, Annu. Rev. Immunol. 31:163-194, 2013; Kennedy et al., J. Exp. Med. 191:771-780, 2000; and Richmond et al., Trends Cell Biol. 15:146-155, 2005). Indeed, failure of interventions to treat anemia associated with RA may limit chances for a fully successful response to treatment.
Thus, there is a medical need unmet by the current treatment options using Jak inhibitors. Efforts to identify Jak1 selective inhibitors are on-going (Zak et al. J. Med. Chem. 2013, 56, 4764-4785; Menet et al. Future Med. Chem. 2015, 7, 203-235; WO2013/007768). Prominent Jak1 selective compounds in development are GLP0634, ABT-494 (WO2015/061665), and the compound in a recent patent publication from Incyte (WO2015/168246), but no Jak1 selective inhibitor has been approved yet.
Herein, novel 1H-furo[3,2-b]imidazo[4,5-d]pyridine derivatives are described as Jak1 selective inhibitors. These compounds, and compositions comprising a compound of this invention are useful in treating disorders related to Jak1 activities such as an autoimmune disease or disorder, or an inflammatory disease or disorder, and a cancer or neoplastic disease or disorder.